Skeletal Metastasis of Prostate Cancer Is Augmented by Activation of EphA2 Noncanonical Signaling and Ligand-Deficient Bone Microenvironment

EphA2, a member of Eph family receptor tyrosine kinases (RTKs), is overexpressed in multiple types of solid human tumors, particularly at the late stages. However, whether and how it drives specific malignant processes remain elusive. We report that EphA2 is elevated during prostate cancer (PCa) progression in multiple syngeneic murine models. Interestingly, human metastatic PCa specimens from two Rapid Autopsy Programs showed selective overexpression of EphA2 in metastasis to the bone, but not to the lymph nodes or viscera. Serine 897 phosphorylation that mediates the pro-oncogenic, noncanonical signaling by EphA2 was also upregulated in bone metastasis. Analysis of human datasets shows EphA2 overexpression is associated with skeletal but not visceral metastases. Ephrin-A1, a major cognate ligand for EphA2, is lost in PCa bone metastasis, which is correlated with poor prognosis. Further, the bone microenvironment is unique in expressing little of the five EFNA genes, providing permissive microenvironment for bone colonization. S897A mutation that ablates EphA2 noncanonical signaling, suppressed PCa development. Restoration of ephrin-A1 expression in PC-3, a model cell line for double negative prostate cancer derived from bone metastasis and devoid of ephrin-As, profoundly changed global tyrosine phosphorylation profiles, inhibited basal ERK and Src activities in vitro, and suppressed tumor development in the bone. Together these results demonstrate EphA2 overexpression and concomitant loss of ligands in PCa lead to activation of noncanonical signaling that is sustained in ephrin-A1-deficient skeletal milieu to promote bone metastasis.